Furfuryl n-morpholine alkyl halide medicinal preparation



aienie .li iifi ATENT YL N-MORPHOLINE ALKYL HALIDE MEDICINAL PREPARATIONin Drawing. Application April 13, rear, Serial No. 136,527

3 Claims.

This invention relates to a medicinal preparation and more icularly toone adapted for oral or parenteral introduction into the human system toeflect a stimulation of the para-sympathetic nervous system. variously,the medicinal preparation in accordance with this invention, active onthe para-sympathetic nervous system, will produce variously a catharticaction, a lowering of the blo pressure, etc.

The medicinal preparation in accordance with this invention will be asolid of high stability and of high solubility in water. ministered tothe human system orally, in tablet form, or parenterally, in aqueoussolution.

Broadly speaking, the medicinal preparation in accordance with thisinvention comprises a quaternary furiuryl alkyl ammonium halide. Morespecifically, the preparation in accordance with this invention maycomprise a quaternary difurfuryl alkyl aonium halide, or again,specifically, a quaternary furfuryl N-morpholine alkyl halide.

The medicinal preparation in accordance with this invention may, forexample, be an iodide, a bromide or a chloride. The alkyl group may bemethyl, ethyl, propyl, isopropyl, butyl, amyl, or the like. n

From the broad standpoint, the medicinal preparation in accordance withthis invention will have the following formula:

in which R. is an alkyl group, as methyl, ethyl, propyl, isopropyl,butyi, amyl, or the like, and in which X is a halide, as iodine,bromine, chlorine, and the like.

The preparation more specifically in the form of a difurfuryl alkvl =1 wonium halide will have the following iormula:

It may be ad-' in which R is an alkyl group, as methyl, ethyl, propyl,isopropyl, butyl, amyl, or the like, and X is a halide, as iodine,bromine, chlorine, or the like.

By way of example of a specific preparation in accordance with thisinvention which has been found to be of desirable therapeutic value and,more particularly, as a stimulator for the parasympathetic nervoussystem, for example, quaternary furfuryl trimethyl iodide may be used byintroduction orally, in tablet form, or parenterally in aqueous solutionwith advantageous result.

The medicinal preparation in accordance with this invention variouslymay be prepared in any suitable manner. Generally speaking, a tertiaryfurfuryl ammonium compound is first prepared and then reacted with analkyl halide to yield a salt of the quaternary amine.

The tertiary furfuryl amines may be prepared by the use of the Leuckartsynthesis known to those skilled in the art and which involves the useof an aldehyde, or a ketone and a formate of an amine, or ammonia, orthe formyl compound derived by dehydration of an amine for- 25 mate.

The production of the preparation in accordance with this invention maybe accomplished by the use of furfural and the for-mates of, rorexample, methyl amine, dimethyl amine, and morpholine, yielding,respectively, furfuryl methyl amine and difurfuryl methyl amine,furfuryl dlmethyl amine and furiuryl N-morpholine amine.

By way oi example of the preparation of difurfuryl methyl amine, 3 molesof methyl amine to 3 moles of formic acid in water are distilled untilthe temperature of the distillate reaches C. Then 2 moles of furfuralare added slowly over a period of one hour, with the distillation ofi ofwater as it forms in the reaction. Carbon dioxide and methyl amine arealso produced during the reaction, which takes place in two stages, asfollows:

i l e CHO+CKaN-CHO CHa-N-OHa-l-CO:

0 Furiuml Formyl methyl Formyl lurlnryl methyl a ns min ami 1$1510 on iL -C CH N-CH CO Q CHO+ 0 OHr I o ao I Diiuriuryl methyl amine After theIurfural has all been added and the reaction has subsided, the residueis cooled, diluted with water, made strongly alkaline and distilleduntil all volatile substances are removed. The distillate is then madeacid with formic acid and distilled with steam as long as non-basicsubstances are carried over by the steam. The residue is then madestrongly basic with caustic soda and the volatile amines again distilledwith steam. The distillate is then treated with strong alkali and thenextracted with ether to extract the mixture of bases. The extract isdried by the addition of caustic potash, the ether removed and theresidual amines separated by distillation.

The two bases obtained by this procedure are furfuryl methyl amine,boiling at 145-150" C., and difurfuryl methyl amine, boiling at 237-238C.

For production of the furfuryl dimethyl amines, moles of dimethyl amineto 5 moles of formic acid and water are distilled to 135 C. to distilloil the water. To the remaining liquid, consisting for the most part ofthe formyl derivative of dimethyl amine, 1 mole of furfural mixed with 1mole of formic acid is added with heating, the temperature beingmaintained at 150-170 C. until the reaction is complete. The reactionmix is then distilled into a receiver. The course of this reaction maybe illustrated as follows:

CH3 CH CH:

The formic acid used in the above reaction functions to react with thedimethyl amine liberated in the reaction.

The final distillate obtained is unchanged dimethyl amide of formicacid, formic acid and furfuryl dimethyl amine. The furfuryl dimethylamine is separated as described above with reference to the separationof furfuryl methyl amine; i. e. by steam distillation from acid solutionand then from alkaline solution, treating the distillate with causticsoda to render it strongly alkaline, extracting the amine with ether,drying and distilling. The furfuryl dimethyl amine boils over the samerange as the mono methyl derivative, 145-150 C.

Furfuryl morpholine amine may be made up in the manner described above,using 5 moles of morpholine and 5 moles of formic acid and reacting withone mole of furfural.

In carrying out the reaction and separating the final product theprocedure described above is followed.

For the preparation of the quaternary compounds, the tertiary amine isdissolved in dry benzene andv to the solution is added one equivalent ofan alkyl halide with inducement of crystallization of the quaternarysalt as, for example, by scratching the side of the vessel containingthe reaction mix, or seeding with a small quantity of the crystallinequaternary salt.

Where pure amine and pure alkyl halide in dry benzene are used, thequaternary salt will separate out in pure form after a' shorter orlonger period, depending on the alkyl halide used.

As has been indicated above, the medicinal preparation prepared inaccordance with this invention will be found to possess excellenttherapeutic properties, more particularly with respect to thepara-sympathetic nervous system. The preparation is a salt of highstability and high water solubility and lends itself to introductioninto the human system orally, for example, in tablet form, orparenterally in aqueous solution.

What I claim and desire to protect by Letters Patent is:

1. A medicinal preparation for effecting stimulation of thepara-sympathetic nervous system comprising a furfuryl N-morpholinealkyl-halide having the following formula:

in which R is an alkyl group from the group consisting of methyl, ethyl,propyl, isopropyl,

, butyl and amyl groups and X is a halide.

2. A medicinal preparation for efiecting stimulation of thepara-sympathetic nervous system comprising a furfuryl N-morpholinealkyl-halide having the following formula:

in which R is an alkyl group from the group consisting of methyl, ethyl,propyl, isopropyl, butyl and amyl groups.

3. A medicinal preparation for efiecting stimulation of thepara-sympathetic nervous system comprising furfuryl N-morpholinemethiodide.

FRED P. NABENHAUER.

